How to administer arginine in a neonate with Necrotizing Enterocolitis (NEC)?

Arginine Supplementation in Neonates with Necrotizing Enterocolitis (NEC)

Arginine supplementation at a dose of 1.5 mmol/kg/day (261 mg/kg/day) should be administered enterally in two divided doses (bid) from the 3rd to the 28th day of life in neonates with NEC to reduce the incidence of severe NEC. 1, 2

Rationale for Arginine Supplementation

• Arginine is the substrate for the production of nitric oxide (a potent vasodilator), which is important for glucose homeostasis and vascular perfusion 1
• Low plasma arginine levels are observed in preterm neonates and may predispose them to NEC 1, 3
• Arginine depletion is related to innate immune suppression that occurs in newborn models of bacterial challenge, impairing pathways critical for immune response 1

Administration Protocol

Enteral Administration (Preferred in NEC)

• Dosage: 1.5 mmol/kg/day (261 mg/kg/day) divided into two doses (bid) 2
• Duration: From the 3rd to the 28th day of life 2
• Route: Enteral administration when feeds are tolerated 1

Parenteral Administration (When Enteral Route Not Available)

• Pediatric Dosage: 0.5 g/kg arginine hydrochloride administered intravenously over 30 minutes 4
• Maximum Dose: Total dose should not exceed 30 g arginine hydrochloride 4
• For patients weighing ≤59 kg: Withdraw a weight-based dose from a sealed bottle and place in a separate container for intravenous infusion 4
• For patients weighing ≥60 kg: The recommended dose is 30 g arginine hydrochloride (300 mL) 4

Evidence Supporting Efficacy

• A double-blind RCT in 152 premature infants showed that arginine supplementation was well tolerated and resulted in a significant decrease in the incidence of NEC (all stages) 1, 5
• A more recent double-blind randomized pilot study demonstrated that enteral L-arginine supplementation of 1.5 mmol/kg/day significantly reduced the incidence of stage III NEC in VLBW infants (2.5% vs 18.6%, p=0.030) 2
• The ESPGHAN/ESPEN/ESPR/CSPEN guidelines provide a conditional recommendation (Level of Evidence: 1-, Recommendation Grade B) that arginine supplementation may be used for prevention of NEC in preterm infants 1

Monitoring and Safety Considerations

• No significant adverse effects directly attributable to arginine supplementation have been observed in clinical trials 2, 6
• Monitor plasma arginine concentrations if possible, as they tend to be lower at the time of NEC diagnosis 3
• Ensure adequate non-protein caloric intake (minimum 30-40 kcal per 1g amino acids) to guarantee amino acid utilization 1
• Monitor for potential side effects, although none have been specifically reported with arginine supplementation in neonates 6

Important Clinical Context

• Arginine supplementation should be considered as part of a comprehensive management approach for NEC that includes:

  • Bowel rest and discontinuation of enteral feeds 7, 8
  • Broad-spectrum antibiotics 7, 8
  • Nasogastric decompression 7, 8
  • Fluid resuscitation and hemodynamic support as needed 7, 8
  • Surgical consultation if perforation or clinical deterioration occurs 7, 8

• When implementing arginine supplementation, ensure that other aspects of nutritional support are maintained through parenteral nutrition during periods of bowel rest 8

Limitations and Future Directions

• While evidence supports arginine supplementation, larger multicenter studies are still needed to further evaluate its efficacy in preventing NEC in VLBW infants 6
• The Cochrane review notes that while there is evidence of benefit, the data are still insufficient for a definitive practice recommendation, highlighting the need for additional research 6